Several publications are referenced in this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these publications is incorporated by reference herein.
Over the past several decades, chemotherapy and radiation therapy coupled with surgery have contributed to a significant reduction in cancer mortality. However, the potential utility of chemotherapeutic drugs in the treatment of cancer has not been fully exploited due to adverse effects associated with the nonspecific cytotoxicity of these agents. Alkylating agents, used alone or in combination with other chemotherapeutic agents, are used in approximately half of all chemotherapy treatments. Alkylating agents interfere with the proliferation of cancerous cells by inhibiting DNA replication. Non-alkylating cancer chemotherapy drugs are also toxic to mammalian cells; they can inhibit multiple sites within a replicating cell, such as (1) synthesis of nucleotides required for DNA replication and (2) microtubule function required for mitosis, to name just two. Radiation therapy, which achieves most of its cell killing properties by generating oxygen radicals within cells, can also efficiently kill mammalian cells. Because the toxic effects of these three commonly used agents are generally not specific to cancer cells, they also affect the growth of normal cells, particularly mitotically active normal cells. As a result, persons being treated with one or more of these cancer therapies commonly develop numerous clinical complications.
Many populations of epithelial cells have a high turnover rate. The toxicity of cancer therapy for epithelial cells accounts for many of the side effects commonly suffered by persons undergoing a regimen of chemotherapy or radiotherapy. These include gastrointestinal distress, nausea, vomiting, diarrhea, loss of appetite, hair loss, bone marrow suppression and skin rash or ulceration at the site of irradiation. These complications can be so difficult to endure that it is not uncommon for people to forego or discontinue recommended cancer therapy treatments in order to avoid the problems. The gastrointestinal disturbances may compromise a patient's chances of recovery, because they make it difficult for him to obtain the nourishment necessary to optimize his ability to fight disease.
Typically, during the course of chemotherapy, the chemotherapeutic agent is administered in sub-optimal doses in order to minimize toxicity and to protect normal, drug-sensitive cells. Reducing the sensitivity of normal cells to chemotherapeutic agents would allow the administration of higher drug dosages and chemotherapy could be rendered more effective.
The successful implementation of protective therapies that promote routine growth and proliferation of normal cells in the presence of radiotherapy or chemotherapeutic agents will allow the use of higher dose aggressive chemotherapy. Two important targets for development of such therapies are (1) the epithelial cells lining the entire gastrointestinal (GI) tract, including the oral mucosa, and (2) the epithelial cells of the skin, including hair follicles and the epidermis.
It appears that chemo- and radiotherapy-associated death and sloughing of GI lumenal cells results in a release of GI damage-associated molecules into the vasculature. These blood-borne molecules, when detected by sites within the brain, trigger the nausea response that is so common among patients receiving Chemotherapy. Present treatments with drugs, such as Ondansetron, serve to suppress these brain centers and thus diminish the nausea response. However, the primary destruction of the GI lining still limits the most effective use of chemotherapy. A better mechanism to diminish nausea in these patients is to eliminate the primary destruction of the GI surface and thus prevent the release of damage-associated, nausea-inducing molecules, rather than just suppressing the effects of these molecules in the brain.
New gastrointestinal therapies are being developed that have afforded some protection to normal cells and have maintained the integrity and function of the tissues made up of these cells. Current approaches to protecting normal cells and stimulating proliferation of normal cells involve nutrient stimulation and maximizing the intake of growth factors. Such strategies have been shown to reduce the severity of toxicity and/or shorten the course of drug treatment. However, in spite of these improvements, serious side effects still persist and more effective therapies are needed.
Investigations have also been made into treatment of chemotherapy-induced alopecia. Alopecia or hair loss is the most common hair growth disorder in humans and is often the cause of great concern in affected individuals. In patients with acquired alopecia associated with cancer chemotherapy or radiation therapy, the loss of hair ranked above vomiting as an important concern. Although this condition is generally reversible and regeneration of hair growth occurs within 1-2 months after discontinuation of treatment, hair loss represents a psychologically distressing effect that can cause negative changes in body image, decreased social activity and altered interpersonal relationships and may lead to refusal of further chemotherapy.
The phenomenon of chemotherapy-induced alopecia is believed to result from cytotoxic and apoptosis related damage to the hair follicle. Several studies have shown evidence that the pathobiologic mechanisms that underlie chemotherapy induced follicle damage are characterized by bulging of the dermal papilla, kinking and distension of the follicular canal and disruption of the melanogenic apparatus.
A variety of approaches have been employed in an attempt to protect patients from chemotherapy-induced alopecia. These have included physical modules that temporarily decrease scalp blood flow and drug contact time with the hair follicle, but the patient tolerance was very poor. These poor results led to the development of scalp cooling methods that decrease both the metabolic rate of follicular stem cells and blood flow to the follicle matrix but this strategy was found to be unsuccessful. The use of dietary α-tocopherol a free radical scavenger, was shown to have a protective effect in rabbits but not in humans. Minoxidil 2% solution was also found to be ineffective in treating chemotherapy induced alopecia. Pre-treatment of rodents with growth factors and cytokines provided some degree of protection against alopecia induced by ARA-C (cytosine arabinoside) but not the commonly used cancer drug cytoxan.
Reversal of cyclophosphamide- or cyclophosphamide/cytarabine-induced alopecia by N-acetylcysteine (NAC) or NAC/ImmuVert, administered parenterally or applied topically in liposomes, has been reported in a rat model system (Jimenez et al., Cancer Investigation 10: 271-276, 1992). NAC is a precursor of glutathione and, as such, is believed to function as a detoxifying agent by increasing intracellular GSH levels. This sort of therapy is limited in efficacy, inasmuch as it has been shown that intracellular GSH levels can only roughly double in a cell by adding exogenous NAC. (See Ho & Fahl, J. Biol. Chem. 259: 11231-11235, 1984; Carcinogenesis 5: 143-148, 1984).
U.S. Pat. No. 5,753,263 to Lishko et al. discloses methods and compositions for treating alopecia induced by certain chemotherapeutic agents, which comprise topical application of an effective amount of a p-glycoprotein, or MDR gene encoding such a protein, in a liposome carrier. This therapy is limited to the particular chemotherapeutic agents that can be exported from a cell via the p-glycoprotein pump. Notably excluded from this list are alkylating chemotherapeutic agents.
Thus, while treatments of the types outlined above may provide some relief from chemotherapy-induced hair loss, their utility is limited; and additional effective therapies are needed.